Interferon-γ:interleukin 4 ratios and associated type 1 cytokine expression in juvenile rheumatoid arthritis synovial tissue

Objective. To compare synovial tissue cytokine mRNA expression between patients with juvenile rheumatoid arthritis (JRA) and a heterogeneous group of non-autoimmune arthropathies (controls) with respect to type 1/type 2 balance. Methods. Thirty-five JRA (average 9.1 years' disease duration) and 13 control synovial tissues were studied. As a measure of the type 1/type 2 cytokine balance in a subset of the IRA and control tissues, interferon-gamma (IFN-gamma) and interleukin 4 (IL-4) mRNA levels were measured by competitive fragment reverse transcription-polymerase chain reaction. To quantitate additional cytokines relevant to this balance, multiprobe ribonuclease protection assays were employed measuring IL-5, IL-10, IL-13, IL-15, IL-18, and IL-12 (p35 and p40 subunits). Immunohistochemistry was performed on JRA tissues using antibodies specific for IL-15 and IL-18. Results. A higher IFN-gamma:IL-4 ratio (p = 0.034) was found in JRA tissues compared to controls. JRA tissues also displayed higher mRNA levels of IL-12p35 (p = 0.021), IL- 15 (p = 0.002), and IL-18 (p = 0.017), but not IL-4 and IL-10. IFN-gamma expression in JRA, but not controls, correlated strongly with IL-12P35 (r = 0,63) and IL-12p40 (r = 0.73) levels. A subset of IL-15+ and IL-18+ cells was detected in IRA synovial tissues, largely within perivascular aggregates. Conclusion. JRA synovial tissue cytokine expression patterns indicate a type 1 bias, even in the later stages of disease. The strong correlation between IFN-gamma and IL- 12 in JRA suggests a prominent role for IL- 12 in promoting the type 1 bias, while IL- 15 and IL- 18 may also indirectly increase IFN-gamma expression and further bias the immune response.